As the global oncology community prepares for the American Association for Cancer Research (AACR) Annual Meeting 2025 with the abstract release this week, the spotlight is on groundbreaking advancements in breast cancer research. This year’s conference promises to showcase innovative therapies, novel biomarkers, and cutting-edge insights into tumor biology that could redefine the future of breast cancer treatment. From the latest in immune checkpoint inhibitors in Triple-Negative Breast Cancer to breakthroughs in HER2 TKI therapies for HER2-mutated Breast Cancer, researchers are pushing the boundaries of what’s possible. In this blog, we discuss snapshots of the most exciting developments presented at AACR 2025, created by Ferma Congress’ new Insights module near-instantly.
Innovative ADC Therapies Transforming Breast Cancer Treatment
Overview: Recent advancements in Antibody-Drug Conjugates (ADCs) have shown significant promise in the treatment of breast cancer (BC), particularly in targeting HER2 and other specific markers. These developments highlight the potential of ADCs to improve efficacy, overcome resistance, and provide durable responses in various subtypes of breast cancer.
- HER2-Targeted ADCs: Enhancing Precision and Efficacy: Trastuzumab-based ADCs, such as Trastuzumab-DM1 and Trastuzumab-Deruxtecan (T-DXd), have demonstrated enhanced efficacy in HER2-expressing breast cancer models. Trastuzumab-DM1 showed superior growth inhibition in HER2-positive cells compared to the payload or antibody alone, while T-DXd exhibited strong anti-tumor activity in multiple patient-derived xenografts (PDX) with 70% and 75% of models showing partial or complete response, respectively. These ADCs also effectively targeted bystander cells, suggesting potential efficacy in heterogeneous tumors 1 2
- Nectin-4 Targeting: A Triple Payload Approach: A novel Nectin-4 targeting ADC with a triple payload (MMAE and dual TOP1 inhibitors) demonstrated high and target-specific cytotoxic activity across all target expression levels. In a high-expressing breast cancer xenograft model, a single dose led to long-lasting and complete tumor regression for over 100 days. This ADC also showed high anti-tumor activity in low Nectin-4-expressing TNBC models, outperforming existing treatments like Enfortumab vedotin and Sacituzumab govitecan 3
- Combating Resistance with Multi-Payload Conjugates: Next-generation Multi-Payload Conjugates™ (MPCs™) targeting HER2 and TROP2 have been developed to address tumor heterogeneity and resistance. These MPCs demonstrated superior inhibition and excellent tolerability in mouse models of HER2 high and HER2 low/TROP2 expressing xenografts, including TNBC. They outperformed current standards of care, such as T-DXd and Sacituzumab govitecan, by achieving tumor elimination at low doses 4
- Real-World Data on ADC Sequencing: A real-world analysis compared the sequencing of Trastuzumab Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG) in HR+/HER2-low and TNBC patients. The study found that using T-DXd followed by SG was more effective than the reverse, with mPFS of 7.09 months for T-DXd followed by 3.08 months for SG in HR+/HER2-low patients. This sequencing strategy also showed better outcomes in TNBC patients 5
Innovative Advances in HER2 TKI Therapies for HER2-Mutated Breast Cancer
Overview: Recent studies presented at the AACR 2025 conference have highlighted significant advancements in HER2-targeted therapies, particularly focusing on HER2 tyrosine kinase inhibitors (TKIs) for HER2-mutated breast cancer. These developments emphasize the efficacy of novel HER2 inhibitors, their impact on brain metastases, and the role of the tumor microenvironment in therapy response.
- Enhanced Efficacy with Novel HER2 Inhibitors: A study on the development of selective HER2 covalent inhibitors by Hanmi Pharmaceutical demonstrated strong anti-tumor activity in brain metastases (BM) and leptomeningeal metastases (LM) models. These inhibitors showed high selectivity over EGFRWT and significantly reduced tumor burden, improving survival in mice with HER2WT-amplified and HER2G776insVG/C mutations. The findings suggest that these inhibitors could effectively manage HER2-driven metastatic complications, addressing a critical unmet need in HER2-altered metastatic diseases. 6
- Role of Tumor Microenvironment in T-DXd Sensitivity: Research on trastuzumab deruxtecan (T-DXd) revealed that its efficacy in HER2-positive cancers is influenced by the tumor microenvironment. The study found that certain cathepsin subtypes, which are lysosomal peptidases, play a critical role in T-DXd sensitivity. Cancer cells exhibited resistance to T-DXd when specific cathepsin subtypes were knocked down, indicating that factors beyond HER2 expression affect T-DXd sensitivity. This highlights the importance of considering the tumor microenvironment in optimizing T-DXd therapy. 7
- Impact of Extrachromosomal DNA (ecDNA) on HER2 Amplification: A study investigating the prevalence of ecDNA in breast cancer found that 22.8% of breast tumors exhibited ecDNA amplifications. The research indicated that ERBB2 (HER2) is prone to amplification on ecDNA in both breast cancer patients and cell lines. These findings suggest that ecDNA could play a role in HER2 amplification and tumor evolution, providing new insights into the mechanisms of HER2-driven breast cancer and potential therapeutic targets. 8
- Dual Inhibition Strategies for Enhanced Treatment: The combination of HER2/EGFR inhibitor lapatinib with CK2 inhibitor silmitasertib showed an additive effect on cell proliferation in ERαY537S mutated breast cancer cells. This combination therapy demonstrated enhanced antiproliferative and anti-migratory effects, suggesting that targeting multiple pathways could improve treatment outcomes for HER2-mutated, endocrine-resistant breast cancer. 9
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